Accuracy of HER2 Status Determination on Breast Core-needle Biopsies (Immunohistochemistry, FISH, CISH and SISH vs FISH)

Laurent Arnould; Pascal Roger; Gaëtan MacGrogan; Marie-Pierre Chenard; André Balaton; Sophie Beauclair; Frederique Penault-Llorca


Mod Pathol. 2012;25(5):675-682. 

In This Article

Abstract and Introduction


Preoperative breast cancer diagnosis on core biopsies has become a standard of care in many countries. Controversies exist concerning the accuracy of HER2 testing on biopsies as compared with surgical specimens, and few data exist concerning the use of emerging technologies such as bright-field in-situ hybridization in such a setting. A French multicenter, cross-sectional, histopathological study assessed the concordance of HER2 status determined by immunohistochemistry and silver (SISH) or chromogenic in-situ hybridization (CISH) on core-needle biopsies with HER2 status determined by fluorescence in-situ hybridization (FISH) on surgical specimens. The concordance between biopsy and operative results was also assessed for each method. We studied 260 breast tumors from 24 centers between April 2003 and August 2009. Excellent concordance (ĸ: 0.92–0.97) was shown between immunohistochemistry and FISH with low discordance rates (2–4%), high specificity (97–98%) and sensitivity values (95–99%), with no significant difference according to the immunohistochemistry interpretation guidelines used. The correlation between SISH and CISH on biopsies and FISH on surgical samples was strong (ĸ: 0.96 and 0.94, respectively), with no significant difference between false negative rates or sensitivity and specificity values (2 and 5%, 99 and 96%, 98 and 98%, respectively). Whatever the evaluation technique, excellent concordance between biopsies and surgical specimens was observed (ĸ 0.97; discordance rates between 1 and 2%), with high sensitivity (98–99%) and specificity (98–100%). Based on these results, when FISH cannot be used, SISH and/or CISH could be proposed as an alternative method to determine HER2 status and to confirm any ambiguous immunohistochemistry results, either for preoperative percutaneous biopsies or for surgical specimens. They could also be used for quality controls and immunohistochemistry calibration.


In non-metastatic breast cancer, knowledge of HER2 status at diagnosis is recommended to determine the adjuvant therapy strategy. It is therefore necessary to have standardized and validated procedures for this evaluation before making any therapeutic decision.

For the HER2 status determination, core-needle biopsies may be less reliable than surgical specimens due to the smaller volume of the tissue sample, the possible sampling error on a tumor with a heterogeneous distribution of the antigens within the tumor, and potential crush/edge artifacts in the core-needle biopsies. However, counter arguments suggest that core-needle biopsies may be better fixed than lumpectomies and should be used to assess the patient's biomarker status. Furthermore, HER2 status is usually homogenous (<3% of heterogeneous tumors)[1] and there is a concrete clinical need for testing core-needle biopsies insomuch as neoadjuvant therapy strategies (and then HER2 status) may be determined for both operable and non-operable breast cancers.

Regarding the available guidelines, ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) recommends that cores entirely involved by retraction artifacts or crush artifacts should not be used as a sample to perform/interpret HER2 immunohistochemistry[2,3] and UK recommendations which precise that observers should be aware of the range of common artifacts, including edge artifacts, which can be problematic in small biopsy samples.[4] French guidelines authorize testing on core biopsies[5] and Canadian recommendations do not specifically discuss core biopsy processing/testing.[6]

Recently, bright-field in-situ hybridization techniques such as chromogenic in-situ hybridization (CISH) and silver-enhanced in situ hybridization (SISH), which combine features of immunohistochemical analysis and in-situ hybridization (ISH), have been introduced for the determination of HER2 status. These new techniques allow results to be visualized by standard bright-field microscopy, and signals do not decay over time.

In most studies, a high correlation (>90%) was shown between the first available procedures designed to evaluate HER2 status (immunohistochemistry, fluorescence in-situ hybridization (FISH), considered as the gold standard, and CISH, first described in 2000)[7] but concordance between these methods might depend, at least in part, on centers (methodology, instrumentation and experience of the laboratories performing the testing), particularly for immunohistochemistry and FISH.[8–11]

SISH was implemented more recently and three studies reported a 97, 96 and 87% concordance between SISH and FISH results on excision samples[12– 14] taking into account that discordant cases could be partly explained by intratumor heterogeneity of amplification. One study showed an 89% concordance of SISH results between surgical specimens and core-needle biopsies but the number of studied cases was limited (n = 56).[15]

Since FISH on surgical specimens is considered as the gold standard for her2 gene status evaluation in breast cancer in the ASCO/CAP guidelines,[2,3] concordance with other available HER2 tests (immunohistochemistry, SISH and CISH), on coreneedle biopsies, is essential because the results could be used for patient's management, and will be the only material available in the neoadjuvant setting.


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